Currently, there are few effective options for the treatment of many common cancer types. The course of treatment for a given individual depends on the diagnosis, the stage to which the disease has developed, and factors such as age, sex, and general health of the patient. The most conventional options of cancer treatment are surgery, radiation therapy, and chemotherapy. Surgery plays a central role in the diagnosis and treatment of cancer. Typically, a surgical approach is required for biopsy and the removal of cancerous growth. However, if the cancer has metastasized and is widespread, surgery is unlikely to result in a cure, and an alternate approach must be taken. Side effects of surgery include diminished structural or organ function and increased risk of infection, bleeding, or coagulation related complications. Radiation therapy, chemotherapy, biotherapy and immunotherapy are alternatives to surgical treatment of cancer (Mayer, 1998; Ohara. 1998; Ho et al., 1998). The disadvantage of many of the alternative therapies are the side effects, which can include myelosuppression, skin irritation, difficulty swallowing, dry mouth, nausea, diarrhea, hair loss, weight loss, and loss of energy (Curran, 1998; Brizel, 1998).
Significant progress in understanding the molecular basis of the immune response to cancer as well as increased understanding of the basic mechanisms of cellular immunology have combined to open new opportunities for the development of effective immunotherapy for patients with cancer (Dudley et al., 2002). Immunotherapy includes both innate and specific immune responses that have the potential to treat different tumor types. The activation of tumor antigen-specific T lymphocytes or non-specific macrophages and natural killer (NK) cells using immunotherapeutic approaches may lead to the destruction of tumor cells (Curiel et al., 2002). Cancer vaccines involve the induction of a specific immune response. However, the administration of a tumor antigen alone is often not sufficient to stimulate an appropriate immune response. Incorporating an immunological adjuvant into a vaccine regimen often improves anti-tumor activity (Dredge et al., 2002).
Lactoferrin is a single chain metal binding glycoprotein. Many cells types, such as monocytes, macrophages, lymphocytes, and intestinal brush-border cells, are known to have lactoferrin receptors. In addition to lactoferrin being an essential growth factor for both B and T lymphocytes, lactoferrin has a wide array of functions related to host primary defense mechanisms. For example, lactoferrin has been reported to activate natural killer (NK) cells, induce colony-stimulating activity, activate polymorphonuclear neutrophils (PMN), regulate granulopoeisis, enhance antibody-dependent cell cytotoxicity, stimulate lymphokine-activated killer (LAK) cell activity, and potentiate macrophage toxicity.
Recombinant human lactoferrin has previously been described as being purified after expression in a variety of prokaryotic and eukaryotic organisms including aspergillus (U.S. Pat. No. 6,080,559), cattle (U.S. Pat. No. 5,919,913), rice, corn, Sacharomcyes (U.S. Pat. No. 6,228,614) and Pichia pastoris (U.S. Pat. Nos. 6,455,687, 6,277,817, 6,066,469). Also described are expression systems for the expression of full-length human lactoferrins (e.g., U.S. Pat. No. 6,100,054). In all cases, part of the teaching is expression of the full-length cDNA and purification of the intact protein whose N-terminal, after processing of the leader peptide, is the amino acid glycine. Nuijens et al. (U.S. Pat. No. 6,333,311) separately describe variants of human lactoferrin but their focus is limited to deletion or substitution of arginine residues found in the N-terminal domain of lactoferrin.
Recently, bovine lactoferrin (bLF) was used as a prophylaxis for tumor formation and/or established tumors. The present invention is the first to use lactoferrin as cancer vaccine adjuvant for the prevention (prophylaxis) or treatment (therapeutic) of tumors.